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Heterozygous SPTAN1 frameshift mutations cause distal myopathy with neurogenic features

ABSTRACT: Spectrinopathies represent an emerging theme with overlapping phenotypes ranging from peripheral or central nervous system involvement towards complex syndromic presentations. A total of 60 different reported SPTAN1 mutations is exemplary for this diversity with phenotypes spanning almost the entire neurospectrinopathy spectrum, except myopathic involvement.Through collaboration within the Solve-RD network we collected patients with unsolved progressive distal weakness and unreported SPTAN1 variants. We reached consensus on the interpretation of clinical picture, electrophysiology, muscle MRI and biopsy. Finally, SPTAN1 protein and RNA expression analysis was performed on available muscle biopsy on one of the patients. We provide evidence for the association of SPTAN1 frameshift variants with childhood onset distal myopathic as well as neurogenic features in 7 patients. This finding further extends the established spectrum of SPTAN1 haploinsufficiency associated with a variable penetrance of hereditary motor neuropathy and ID. Overlap between distal myopathic and neurogenic features could be present in other patients and may be overlooked due to phenotypic similarity.

ORGANISM(S): Homo sapiens

PROVIDER: GSE259351 | GEO | 2026/05/01

REPOSITORIES: GEO

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Project description:Abstract Background Vertebral endplate signal intensity changes visualized by magnetic resonance imaging termed Modic changes (MC) are highly prevalent in low back pain patients. Interconvertibility between the three MC subtypes (MC1, MC2, MC3) suggests different pathological stages. Histologically, granulation tissue, fibrosis, and bone marrow edema are signs of inflammation in MC1 and MC2. However, different inflammatory infiltrates and amount of fatty marrow suggest distinct inflammatory processes in MC2. Aims The aims of this study were to investigate i) the degree of bony (BEP) and cartilage endplate (CEP) degeneration in MC2, ii) to identify inflammatory MC2 pathomechanisms, and iii) to show that these marrow changes correlate with severity of endplate degeneration. Methods Pairs of axial biopsies (n=58) spanning the entire vertebral body including both CEPs were collected from human cadaveric vertebrae with MC2. From one biopsy, the bone marrow directly adjacent to the CEP was analyzed with mass spectrometry. Differentially expressed proteins (DEPs) between MC2 were identified and bioinformatic enrichment analysis was performed. The other biopsy was processed for paraffin histology and BEP/CEP degenerations were scored. Endplate scores were correlated with DEPs. Results Endplates from MC2 were significantly more degenerated. Proteomic analysis revealed an activated complement system, increased expression of extracellular matrix proteins, angiogenic, and neurogenic factors in MC2 marrow. Endplate scores correlated with upregulated complement and neurogenic proteins. Discussion The inflammatory pathomechanisms in MC2 comprises activation of the complement system. Concurrent inflammation, fibrosis, angiogenesis, and neurogenesis indicate that MC2 is a chronic inflammation. Correlation of endplate damage with complement and neurogenic proteins suggest that complement system activation and neoinnervation may be linked to endplate damage. The endplate-near marrow is the pathomechanistic site, because MC2 occur at locations with more endplate degeneration. Conclusion MC2 are fibroinflammatory changes with complement system involvement which occur adjacent to damaged endplates.

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Heterozygous SPTAN1 frameshift mutations cause distal myopathy with neurogenic features

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